Method for pulmonary and oral delivery of pharmaceuticals

ABSTRACT

In a powder formulation for use in a dry powder inhaler, a pharmaceutical acts as its own carrier, so that use of lactose or other excipients are not needed. The dry powder formulation has a single active pharmaceutical compound having two major populations in particle size distribution: microfine particles of the active pharmaceutical, of 1-10 microns in diameter, and larger carrier particles, also of the active pharmaceutical compound. The carrier particles provide a long acting, delayed onset, and optionally therapeutic effect via the GI tract, while the microfine particles provide a fast onset effect via the lung.

[0001] This is a divisional of U.S. patent application Ser. No.09/480,549, filed Jan. 10, 2000, now pending, and incorporated herein byreference.

BACKGROUND OF THE INVENTION

[0002] The field of the invention is inhalers and pharmaceuticalformulations for use in inhalers.

[0003] Dry powder inhalers have been successfully used to deliverpharmaceuticals into the lungs, primarily for treatment of asthma andother pulmonary conditions. Use of an inhaler for delivery of apharmaceutical is advantageous as it is relatively simple, fast,comfortable, and pain-free for the patient. Due to the nature of theabsorption within the lungs, inhaled pharmaceuticals tend to be veryfast acting. Inhalation usually provides a very fast rise of the levelof the pharmaceutical in the blood, when compared to other deliverytechniques, such as oral or transdermal delivery. For example, albuterolis a bronchodialator which acts rapidly when inhaled to treat an asthmaattack, a condition for which treatment with a solid oral dosage formmay be too slow. While this rapid absorption is often advantageous, itcan also require relatively frequent dosing via inhalation, to provide asustained effect. In contrast, oral delivery, which provides absorptionof the drug via the gastrointestinal (GI) tract, generally provides amuch more slowly acting, but also often a more sustained, therapeuticeffect. For many pharmaceuticals, the delay in the onset of thetherapeutic effect is a significant disadvantage.

[0004] Thus, each pharmaceutical delivery route (via the GI tract, andvia inhalation into the lungs) has advantages and disadvantages,depending on the pharmaceutical used and the therapeutic effect desired.However, the advantages of each route have not, until now, beencombined, to achieve the advantages of both routes, in a single dose orstep.

[0005] Many patients must regularly take two or more pharmaceuticals.The pharmaceuticals may act independently to treat unrelated conditions,or they may act together, or complement each other, in treating a singlecondition. The dosing regimen for combinations of pharmaceuticals oftenrequire that they be taken at the same time. This may require taking 2or more capsules or tablets from different bottles, a combination ofsuch oral dose forms and a pharmaceutical delivered via another route,or some other combination of delivery routes. For example, patients withType 2 diabetes will often be prescribed doses of insulin, viainjection, along with a hypoglycemic drug in an oral dose form.

[0006] The need for separate dosing is less convenient for the patientthan taking a single dose. The patient must: maintain a supply of both(or all) of the separate pharmaceuticals; remember to take each one; andgo through the separate actions of taking each one. Accordingly, thedosing regimen is more complicated, and difficult to maintain (whencompared to a single dosing regimen), especially for classes of patientshaving a disability due to sickness, injury, age, or medical condition.

[0007] For patients taking more than one pharmaceutical, complying withtheir prescribed dosing regimen can be less consistent, due to the needto separately take each of the pharmaceuticals. To achieve the fulltherapeutic effect of the prescribed pharmaceuticals, it is generallyimportant to maintain consistent compliance. Thus any pharmaceuticaldelivery techniques which can improve patient compliance will help toimprove the patients health. Consequently, for many patients, it wouldbe highly advantageous to be able to combine separate dosing regimensinto a single joint dosing regimen. Reducing multiple dosing regimens toa single dosing regimen improves the convenience to the patient, andmakes compliance to the prescribed dosing regimen easier, and thus morelikely to be consistently followed.

[0008] Accordingly, it is an object of the invention to provide apharmaceutical formulation for use in an inhaler, which provides therapid onset or effect of an inhaled pharmaceutical, along with theslower onset and/or the longer acting effect of a pharmaceuticaldelivered via the GI tract.

[0009] It is a further object of the invention to provide apharmaceutical formulation for use in an inhaler which can combinemultiple dosing regimens into a single action, to improve theconvenience to the patient, and to improve patient compliance to theprescribed dosing regimen.

SUMMARY OF THE INVENTION

[0010] In a first aspect of the invention, a pharmaceutical formulationincludes microfine active particles preferably of about 1-10 microns indiameter and carrier particles preferably of about 10-100 or larger, andpreferably greater than 50 microns in diameter. The microfine particlesand the carrier particles are both made of an active pharmaceuticalcompound. The carrier particles and the microfine particles may be thesame active pharmaceutical compound, or they may be different activepharmaceutical compounds. At least some of the microfine particles maybe attached to and carried by the larger carrier particles.

[0011] In a second aspect of the invention, upon inhalation, themicrofine particles and carrier particles are separated, preferablythrough input of mechanical or electrical energy. The microfineparticles travel through the throat and pass into the lungs. The carrierparticles pass into the throat, and are swallowed. Accordingly, activepharmaceuticals are delivered to both the lungs (for a rapid onset orfast acting effect) and to the GI tract (for a slower onset or a moresustained effect). The swallowed dose is preferably at least 10 timesgreater in weight than the inhaled dose, and preferably is at least 50,100, or even 1,000 times greater.

DETAILED DESCRIPTION OF THE INVENTION

[0012] In a first embodiment of the invention, a dry powder formulationfor use in a dry powder inhaler has a pharmaceutical which acts as itsown carrier. The formulation has a single active pharmaceuticalcomponent, formulated such that it has two major populations in theparticle size distribution. The first population includes larger activecarrier pharmaceutical particles, e.g., 10-2000 microns in diameter,preferably 30-300 microns in diameter, and most preferably 50-100microns in diameter (average volume median diameter).

[0013] The second population includes microfine active pharmaceuticalparticles, of 1-10 microns in diameter, and preferably 1-5 microns indiameter.

[0014] At least some of the microfine particles attach themselves to thecarrier particles, due to surface interactions, as is well known in theparticle technology field. Consequently, in this embodiment, the activecarrier particles carry the microfine particles, in much the same way asan excipient, such as e.g., lactose in conventional formulations.However, since the carrier particles also comprise an activepharmaceutical compound, the disadvantages of using lactose(interactions with the pharmaceutical and/or water vapor) are avoided,while aerosol performance is maintained. In addition, the delayed onsetand/or sustained therapeutic benefits of delivery of the active carrierparticles to the GI tract, are obtained.

[0015] The single component formulation described above can be used inthe same way as conventional microfine active pharmaceutical/lactose orother excipient formulations. However, with convention formulations,after inhalation, the lactose serves no purpose. The lactose orexcipient particles, generally exceeding the particle size range forinhalable particles (e.g., 1-10 microns), impact the mouth or throat,and are then swallowed, with no added therapeutic result.

[0016] The onset of the therapeutic effect provided by these carrierparticles will be delayed relative to the therapeutic effect provided bythe microfine particles, with all or almost all drugs. The duration ofthe therapeutic effect provided by the carrier particles may becomparable to, or greater than the duration of the therapeutic effectprovided by the microfine particles. The delayed onset extends the totalcombined duration of the inhaled/swallowed dose. The carrier particlesmay also be prepared (e.g., coated) so that they provide a sustained,long duration therapeutic effect.

[0017] In contrast, with the single component formulation of theinvention, as described above, the carrier particles, which impact themouth or throat, and are swallowed, are active drug particles, which adda therapeutic effect, via absorption by the GI tract. If the specificpharmaceutical used in the single component formulation is notabsorbable, then the active pharmaceutical carrier particles will notprovide any added therapeutic effect via the GI tract. However, thedisadvantages of including a sugar excipient, e.g. lactose, are stillavoided. On the other hand, if the specific pharmaceutical is absorbablevia the GI tract, then the additional therapeutic effect through the GItract is achieved.

[0018] In prior known formulations used with inhalers, some active drugparticles may be deposited in the throat and swallowed. However, theamount swallowed does not, and is not intended to, provide a therapeuticeffect. These known formulations, used with existing inhalers, such asthe Rotohaler® dry powder inhaler, generally have not deliveredsufficient dry powder into the GI tract to provide a therapeutic effect.Indeed, their objective is to deliver all of the powder into the lungs.The powder delivered to the GI tract has been delivered to the throatonly due to inefficiencies in the inhaler technology and formulations.

[0019] In the present formulation, generally the dose delivered to theGI tract will be much greater, e.g. 10-50, 10-100, or 10-1,000 timesgreater (by weight) than the dose delivered to the lungs. For example,with albuterol, the oral dose may be 10 milligrams, whereas the dose tothe lungs may be 100 micrograms. The dose to the lungs provides a rapidonset (i.e., within 30 minutes, and preferably within 15, 10, or even 5minutes) therapeutic effect. The dose to the GI tract provides a delayedor slower onset, i.e., providing a therapeutic effect which typicallybegins to occur in greater than 30 minutes.

[0020] The combined delivery to both the lung and the GI tract isespecially useful for drugs or pharmaceutical compounds where both fastand slower and/or sustained action is beneficial, for example, with painrelief drugs. With the single component formulation described above,very fast therapeutic action is obtained from the absorption of themicrofine particles passing into the lung. In addition, slower onset,optionally with longer term therapeutic effects, are obtained from theactive pharmaceutical carrier particles deposited in the mouth orthroat, swallowed, and then absorbed via the GI tract. The carrierparticles may be coated to provide improved sustained release. Thus thepresent formulation provides a therapeutic effect which is faster thanoral delivery alone. It may also provide, with some pharmaceuticals, atherapeutic effect which is longer acting than conventional inhaledformulations.

[0021] In a two component embodiment of the invention, the carrierparticles and microfine particles are different active pharmaceuticalcompounds. Specifically, the pharmaceutical compound of the carrierparticles is selected to provide for absorption via the GI tract, whilethe pharmaceutical compound for the microfine particles is a differentpharmaceutical compound intended for delivery to the lung. An example ofa 2 component embodiment is insulin as the microfine particles, and oralhypoglycemics or mimetics as the carrier particles. Multiple componentformulations, having several active pharmaceutical microfine particlesand carrier particles, may also be used. In another embodiment, themicrofine particles may be substantially separated (not attached to) thecarrier particles.

[0022] The formulations described above are useful with a wide range ofdrugs including beta-agonists such as albuterol; anti-inflammatories;analgesics; narcotics; anti-hypertensives; drugs for treating: motionsickness, pain, cancer, COPD, antiemetics, and others. The formulationsof the invention contemplate use of potent drugs as the microfinecomponent, consistent with the delivery of small doses to the lung.Inhaled doses generally cannot exceed 50 mg in a single dose, withoutcausing the patient to cough. Hence, the microfine particle componentshould range from a few micrograms up to 50 mg in a single inhaled dose.The microfine particles are also preferably not irritating to the lung.On the other hand, the oral component, i.e., the carrier particles, cancomprise a much larger dose. The carrier particles are also preferablycompatible with GI tract delivery.

[0023] The present formulation is preferably delivered using a highefficiency inhaler, such as described in U.S. Pat. Nos. 5,577,497;5,622,166; and WO 98/03217, incorporated herein by reference.Preferably, at least 20%, and more preferably, at least 30% or even 40%of the microfine component of the dose emitted from the inhaler isrespirable.

[0024] Thus, a novel dry powder formulation and inhalation method havebeen described. Various changes and uses of substitutes may of course bemade, without departing from the spirit and scope of the invention. Theinvention, therefore, should not be limited, except by the followingclaims, and their equivalents.

What is claimed is:
 1. A method for simultaneous delivery of atherapeutically active amount of a powder formulation to both the lungsand the gastrointestinal tract of a patient comprising the steps of:preparing a formulation of a pharmaceutical powder comprising activecarrier particles and active microfine particles; loading theformulation into a dry powder inhaler; inhaling the formulation, with atherapeutically effective amount of the carrier particles passing intothe patient's gastrointestinal tract.
 2. The method of claim 1 whereinthe formulation is substantially free of any excipient.
 3. The method ofclaim 1 wherein the formulation comprises a pure single pharmaceuticalcompound.
 4. The method of claim 1 wherein the microfine particles andthe carrier particles are different pharmaceutical compounds.
 5. Themethod of claim 1 wherein the microfine particles comprise at least onepharmaceutical compound, and the carrier particles comprise at least onepharmaceutical compound.
 6. The method of claim 1 wherein the carrierparticles have an average volume median diameter of 20-2000 microns andthe microfine particles have an average volume median diameter of 1-10microns.
 7. The method of claim 1 wherein the inhaled microfineparticles in the lung provide a fast acting therapeutic effect, and thecarrier particles in the gastrointestinal tract provide a delayed onsetof action therapeutic effect.
 8. The method of claim 1 wherein theformulation comprises inactive excipient particles.
 9. The method ofclaim 8 wherein the inactive excipient particles have an average volumemedian diameter of 1-250 microns.
 10. The method of claim 1 wherein thedose delivered to the GI tract is 10-1,000 times greater than the dosedelivered to the lungs.
 11. The method of claim 7 wherein the particlesin the lung provide a therapeutic effect within 15 minutes afterinhalation and the particles in the GI tract provide a therapeuticeffect which lasts for more than 30 minutes.
 12. The method of claim 1wherein the formulation has more particles in the size distribution of1-10 microns average volume median diameter and in the size distributionof 30-300 microns average volume median diameter than in the sizedistribution range between 10 and 30 microns.
 13. The method of claim 1wherein the formulation has more particles in the size distribution of1-10 microns average volume median diameter and in the size distributionof 50-100 microns average volume median diameter than in the sizedistribution range between 10 and 50 microns.
 14. The method of claim 1wherein the formulation has more particles in the size distribution of1-5 microns average volume median diameter and in the size distributionof 30-300 microns average volume median diameter than the sizedistribution range between 5 and 30 microns.
 15. The method of claim 1wherein the formulation has more particles in the size distribution of1-5 microns average volume median diameter and in the size distributionof 50-100 microns average volume median diameter than in the sizedistribution range between 5 and 50 microns.
 16. The method of claim 1further including the step of coating the carrier particles to provide asustained therapeutic effect.
 17. The method of claim 1 wherein theweight ratio of carrier particles to microfine particles ranges from10/1 to 1000/1.
 18. The method of claim 1 wherein the microfineparticles comprise insulin and the carrier particles comprise an oralhypoglycemic or mimetics.
 19. The method of claim 1 wherein the weightof the microfine particles does not exceed 50 mg.
 20. The method ofclaim 1 wherein the carrier particles have an average diameter of from20-2000 microns average volume median diameter.
 21. The method of claim1 wherein the carrier particles have a size ranging from 30-300 micronsaverage volume median diameter.
 22. The method of claim 1 wherein thecarrier particles have a size ranging from 50-100 microns average volumemedian diameter.
 23. A method for simultaneous delivery of apharmaceutical formulation to both the lungs and the gastrointestinaltract, comprising the steps of: preparing a formulation of asubstantially pure dry pharmaceutical powder including active inhalableparticles having a diameter of 1-10 microns average volume mediandiameter and including carrier particles having at least 30 micronsaverage volume median diameter, and with the carrier particlescomprising the same pharmaceutical compound as the active particles;loading the formulation into a dry powder inhaler; and inhaling theformulation.